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Targeted Enhancer Activation by a Subunit of the Integrator Complex.
Elisa Barbieri1, Marco Trizzino1, Sarah Ann Welsh2
1The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Molecular Cell
|July 17, 2018
Summary
The Integrator INTS13 subunit acts as a monocytic differentiation factor by targeting enhancers with Early Growth Response (EGR) transcription factors. This reveals a novel enhancer regulatory axis controlling myeloid cell development.
Area of Science:
- Epigenetics and Gene Regulation
- Cell Fate Determination
- Transcription Factor Function
Background:
- Cell fate control is an epigenetic process driven by transcription factors (TFs) and recruited activators.
- Current understanding posits lineage specificity arises solely from TF-DNA motif interactions, with activators being passive.
Purpose of the Study:
- To investigate the role of INTS13, a subunit of the Integrator complex, in monocytic/macrophagic differentiation.
- To elucidate the functional specificity of the Integrator complex and its TF-specific regulatory potential.
Main Methods:
- Investigated INTS13's function as an independent sub-module targeting enhancers via Early Growth Response (EGR1/2) TFs and NAB2.
- Assessed chromatin looping and activation at poised monocytic enhancers upon INTS13 binding.
- Examined the impact of INTS13, EGR1, and NAB2 depletion on monocytic differentiation in cell lines and primary human progenitors.
Main Results:
- INTS13 functions as a monocytic differentiation factor, targeting enhancers through EGR1/2 TFs and NAB2.
- INTS13 binding to poised monocytic enhancers induces chromatin looping and activation.
- Depletion of INTS13, EGR1, or NAB2 significantly impairs monocytic differentiation.
Conclusions:
- The Integrator complex is not functionally homogeneous and possesses TF-specific regulatory capabilities.
- A novel enhancer regulatory axis involving INTS13, EGR1/2, and NAB2 controls myeloid differentiation.
- This discovery redefines the understanding of lineage specificity and activator roles in epigenetic gene regulation.
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